1. Field of the Invention
This invention relates to a coating material for controlling drug release, useful for long acting formulations--e.g. for once-a-day administration, and to a long acting granular composition comprising a drug (especially one conventionally difficult to prepare in long acting form) coated with said coating material. This composition may be mixed with other granular drug formulations--e.g. of different maintainance and/or initial rate or delay of drug release such as granular semi-long acting pharmaceutical praparations and/or granular gastric juice-soluble pharmaceutical preparations.
2. Description of the Related Art and Problems to be solved
Long acting formulations have many advantages for medical treatment, since the dosing frequency is decreased and this increases compliance with the prescribed dosing regime. Various types of formulation have been investigated in order to develop a long acting formulation. However, for many drugs it has been easy to develop a sufficiently long acting formulation, especially one which gives effective drug concentration in the blood rapidly after administration and maintains constant drug concentration in the blood for a long time.
The residence time of orally administered drug in the small intestine is about 2 to 6 hours, and absorption rate through the gastrointestinal tract varies greatly along the tract. Generally, drugs are poorly absorbed in the gastric portion, and are mainly absorbed in the small intestine. The drug absorption rate decreases in the order of duodenum, jejunum and ileum, and the drug is absorbed in the large intestine (specifically, colon) hardly at all or at a very low rate. Hence, in designing a long acting formulation, consideration must be given to the kind of drug and to the absorportion characteristics of the gastrointestinal tract. Various methods have hitherto been investigated in attempts to solve such problems.
A typical example is a binary thermodynamic penetration device of Alza Corp. (Japan Kokai No. 41609 (1985)). The device provides a penetration chamber having a partition wall and composed of at least partially semipermeable material. The formed separated chambers contain first and second penetration compositions, respectively. A passageway passes through the chamber from the outside to the first penetration composition to send the drug outside. The device can continuously send out a definite amount of the drug at a desired site of the body and independent from the pH in the body (the 0 order release). However, drugs which are highly dependent on the properties of the absorption site or liable to be metabolized cannot be sufficiently absorbed by the 0 order release type long acting pharmaceutical preparations.
Nicardipine (generic name) hydrochloride is deemed difficult to formulate as a long acting preparation, but we have previously obtained a somewhat long acting formulation (see unexamined Japanese Patent Publication No. Sho. 58-116414) by coating small granular nuclei such as Nonpareil [trade name] with nicardipine hydrochloride, entero- and/or gastrosoluble base material and a surface active agent, and further coating the product with a drug-release controlling material such as Eudragit RL [trade name, made by Rohm and Haas Co., a 1:2:0.2 ethylacrylate/methylmethacrylate/trimethylammonioethylmethacrylate chloride copplymer]. This granular formulation has been put to practical use as a fairly long acting preparation for twice-a-day administration, but cannot be used satisfactorily for once-a-day administration. We have conducted various investigations for the purpose of obtaining a once-a-day oral administration-type formulation for drugs which are difficult to prepare in satisfactory long acting form, and have obtained a drug-release controlling coating material by mixing, in a specific ratio, specific water-insoluble and low water-permeability polymer [a] and at least two materials (usually polymers) [b] [c] differing from each other in the pH-dependency of their solubility, namely, pH-dependent materials, (e.g. being soluble only at pH values above 6 and 7 respectively), and have discovered that the thus obtained drug-release controlling coating material unexpectedly can give excellent medicament-dissolution results.
All parts and percentages herein are by weight unless otherwise specified.